Method and apparatus for coating a medical device by electroplating

ABSTRACT

Methods and apparatuses for coating surfaces of medical devices by electroplating are disclosed. In one embodiment, the invention includes a coating method in which a mixture of a therapeutic agent, and a plating material are electroplated onto the surface of the medical device. The electroplating method may be performed at a relatively low temperature to avoid destruction of the therapeutic agent. In another embodiment, a coating method is disclosed in which the coating is formed by suspending a therapeutic agent in an electrolytic solution and electroplating a plating material onto the medical device wherein the plating material carries the suspended therapeutic agent. Thus, the coating of plating material contains the suspended therapeutic agent. These methods and apparatuses are used to apply one or more coating materials, simultaneously or in sequence by varying the electroplating voltage. In certain embodiments of the invention, the coating materials include therapeutic agents and cationic drugs.

FIELD OF THE INVENTION

The present invention relates to the coating of medical devices.

BACKGROUND OF THE INVENTION

The positioning and deployment of medical devices within a target siteof a patient is a common, often-repeated procedure of contemporarymedicine. These devices or implants are used for innumerable medicalpurposes including the reinforcement of recently re-enlarged lumens, thereplacement of ruptured vessels, and the treatment of disease such asvascular disease by local pharmacotherapy, i.e., delivering therapeuticdrug doses to target tissues while minimizing systemic side effects.Such medical devices are implanted or otherwise utilized in body luminaand organs such as the coronary vasculature, esophagus, trachea, colon,biliary tract, urinary tract, prostate, brain, and the like.

Coatings are often applied to the surfaces of these medical devices toincrease their effectiveness. These coatings may provide a number ofbenefits including reducing the trauma suffered during the insertionprocedure, facilitating the acceptance of the medical device into thetarget site, and improving the post-procedure effectiveness of thedevice.

Coating medical devices also provides for the localized delivery oftherapeutic agents to target locations within the body, such as to treatlocalized disease (e.g., heart disease) or occluded body lumens. Suchlocalized drug delivery avoids the problems of systemic drugadministration, such as producing unwanted effects on parts of the bodywhich are not to be treated, or not being able to deliver a high enoughconcentration of therapeutic agent to the afflicted part of the body.Localized drug delivery is achieved, for example, by coating expandablestents, grafts, or balloon catheters, which directly contact the innervessel wall, with the therapeutic agent to be locally delivered. Stentsare often used to support tissue while healing takes place. Expandablestents are tube-like medical devices that often have a mesh-likepatterned structure designed to support the inner walls of a lumen.These stents are typically positioned within a lumen and, then, expandedto provide internal support for it. For example, an intraluminalcoronary stent may be used during a coronary bypass graft surgery, orother heart surgery, to keep the grafted vessel open to prevent thereclosure of the blood vessel. The coating on these medical devices mayprovide for controlled release, which includes long-term or sustainedrelease, of a therapeutic agent.

Aside from facilitating localized drug delivery, medical devices arecoated with materials to provide beneficial surface properties. Forexample, medical devices are often coated with radioopaque materials toallow for fluoroscopic visualization during placement in the body. It isalso useful to coat certain devices to achieve enhanced biocompatibilityand to improve surface properties such as lubriciousness.

Conventionally, coatings have been applied to medical devices byprocesses such as dipping and spraying. Dipping and spraying processesusually cannot apply multiple layers of different coatings withoutrequiring appropriate drying time between coating steps, which canincrease production time and costs. Further, dipping and sprayingprocesses may result in uneven coating thickness.

There is, therefore, a need for a cost-effective method for coating thesurface of medical devices that results in even and uniform coatings andmeasured drug doses per unit device. The present invention providesmethods and apparatus for coating medical devices by electroplating aplating material with a therapeutic agent onto the surface of medicaldevices. The methods of the present invention permit direct localdelivery of therapeutic agents to targeted diseased locations,minimizing waste and loss of expensive therapeutic. The methods alsoallow the coatings to have uniform thicknesses and mechanicalproperties, and uniform drug dose.

SUMMARY OF THE INVENTION

The present invention regards a method and apparatus for coating atleast a portion of a medical device (e.g., a stent). In accordance withone embodiment, a method for applying at least a portion of a coatingmaterial on a medical device having a surface is provided. This methodincludes forming a coating on a bio-compatible medical device byelectroplating a mixture of a therapeutic agent, and a plating materialonto the surface of the medical device. The electroplating may beperformed at a relatively low temperature.

In another embodiment of the present invention, a method for applying atleast a portion of a coating to a bio-compatible medical device isprovided wherein the coating is electroplated onto the surface of themedical device and formed by varying the electroplating voltage toregulate the amount of the therapeutic agent and the amount of platingmaterial that is coated.

In another embodiment of the present invention, a method for applying atleast a portion of a coating to a bio-compatible medical device isprovided wherein the surface of the medical device is treated, e.g.creating a porous surface layer, to increase the amount of thetherapeutic agent that may be electroplated onto the medical device. Thecoating is formed by electroplating a therapeutic agent into and/or ontothe porous surface layer.

In another embodiment of the present invention, a method for applying atleast a portion of a coating to a bio-compatible medical device isprovided wherein the coating is formed by suspending a therapeutic agentin an electrolytic solution and electroplating a plating material ontothe medical device wherein the plating material carries the suspendedtherapeutic agent such that the coating of plating material contains thesuspended therapeutic agent.

In another embodiment of the present invention, an apparatus forapplying a coating to a medical device having a surface is providedwherein the coating is formed by electroplating a mixture of atherapeutic agent and a plating material.

The present invention provides methods and apparatus for coating medicaldevices having a surface by electroplating a plating material with atherapeutic agent onto the surface of medical devices. The methods ofthe present invention permit coating the external surface of the medicaldevices, which, for example, directly contacts the diseased vessel wall,thereby permitting direct local delivery of therapeutic agents totargeted diseased locations. The methods also minimize wasted coatingduring the coating process, thereby minimizing the loss of expensivetherapeutic. The methods also allow the coatings to have uniformthicknesses and mechanical properties, and uniform drug dose.

Alternate embodiments of the present invention also permit applicationof multiple layers of coating material by varying the electroplatingvoltage to regulate the amount of a first therapeutic agent, at least asecond therapeutic agent, and a plating material. These methods of thepresent invention are time efficient and cost effective because theyfacilitate the uniform application of multiple layers of coatingmaterials in a single coating process without requiring any intermediatedrying step between the application of coating layers. This results inhigher process efficiency.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an electroplating apparatus for coating medicaldevices in accordance with a first embodiment of the present invention.

FIG. 2 illustrates an electroplating apparatus for coating medicaldevices in accordance with an alternative embodiment of the presentinvention.

DETAILED DESCRIPTION

FIG. 1 illustrates an apparatus for coating a medical device having asurface in accordance with one embodiment of the present invention. Theapparatus in this embodiment, as shown in FIG. 1 and generallydesignated as 10, provides for depositing a coating on a medical device20 by electroplating a mixture of a therapeutic agent and a platingmaterial. The coating material is electroplated onto an external surface21 of medical device 20. The medical device 20 can be, for example, astent having a patterned external surface as shown in FIG. 1.

As depicted in FIG. 1, the apparatus for coating a medical device byelectroplating 10 includes an electroplating cell 30, cathode 40, anode50, and voltage source 60. The electroplating cell 30 contains anelectrolytic solution 31. The portion of the medical device 20 to becoated is positioned in the electrolytic solution 31 withinelectroplating cell 30 and electrically connected to voltage source 60with a cathode wire 61. The medical device 20 serves as a cathode 40, ornegatively charged electrode, of the electroplating cell 30, and iselectrically connected to the negative pole of voltage source 60.Voltage source 60 may be a source that delivers constant or varyingvoltage. In FIG. 1, voltage source 60 is shown as a battery.

Referring again to FIG. 1, the plating material 51 is also placed in theelectrolytic solution 31 and electrically connected to voltage source 60with an anode wire 62. The plating material 51 serves as an anode 50, orpositively charged electrode, of the electroplating cell 30, and iselectrically connected to the positive pole of voltage source 60. Aperson of ordinary skill in the art will appreciate that a variety ofelectrical connection devices may be used as the cathode wire 61 oranode wire 62, to permit the flow of electrical charges between thevoltage source 60 and cathode 40 or anode 50 respectively, such ascopper wire or wire made from any other conductive material. The medicaldevice 20 may be made from any bio-compatible metal or alloy. Typically,medical devices, e.g. stents, are made from stainless steel, tantalum,platinum, cobalt chrome alloys, elgiloy or nitinol alloys. The platingmaterial 51 can be the same or different metal or alloy as that of themedical device to be coated. Examples of plating materials include, butare not limited to, gold, titanium, halfnium, zirconium, iridium,alumina, and niobium, as well as the oxides of some of those materials.The plating material may be a noble metal, such as platinum, forradioopacity characteristics.

One of ordinary skill in the art will appreciate that a variety of acidor salt solutions may be used as the electrolytic solution 31 to ionizethe therapeutic agent and carry ions of the plating material. Theelectrolytic solution 31 may be a solution of an acid or salt of theplating metal 51. For example, Pd salt, or Pd(NH₃)₂(NO₂)₂, in anammoniacal bath medium may be used. Solutions containing 5-10 gms/literof Pd, operated at 40-50 C, using fairly low current density of 0.5amps/dm² can produce coatings having 200-300 DPN and a thickness of upto 5 microns. Ammonium phosphate or sulfamate may also be used asconducting salts. In addition, the electrolytic solution may contain Pdchelates. This electrolytic solution may contain 5-10 gms/liter of Pd,buffered with monopotassium phosphate, and can produce very brightcoatings over a wide range of operating solution conditions (e.g., pH of4-12). In addition, an electrolyte containing Pd ammine salts (e.g.,Pd(NH₃)4×) in a solution of up to 30 gms/liter of Pd maintained at a pHof 9, a temperature of 50 C, and a current density of 4 amps/dm² may beused to obtain high ductile coatings with low internal stresses at highdeposition rates. The properties of the deposited coating may be variedfrom the previously expressed conditions by varying the electrolytecomposition, agitation, temperature, pH, metal loading, current density,and voltage wave form. For example, if a high density coating depositionis desired, the metal ion concentration may be raised, the currentdensities may be lowered, and a mild to moderate agitation should beintroduced. If a porous or less dense deposition is desired, then thesesame parameters may be changed in the opposite direction. However, askilled artisan would appreciate that the acid or salt solution selectedshould not destroy the dissolved therapeutic agent.

Referring to FIG. 1, the portion of the medical device 20 to be coatedis immersed in the electrolytic solution 31 in the electroplating cell30. The medical device 20 may be freely immersed in electrolyticsolution 31 or secured by a holder (not shown). The holder can be, forexample, an inflatable balloon or a mandrel which secures the medicaldevice by exerting a force upon the internal surface of the medicaldevice, thereby permitting the external surface to be plated. It will beappreciated by one of ordinary skill in the art that a variety of holderdevices can be designed to secure the medical device and permit accessto portions of surface.

By holding the medical device 20 from its internal surface with a holderextending the length of the medical device, the holder may mask theinternal surface, thereby preventing the coating material from adheringto the internal surface, if desired. Alternatively, if it is desired tocoat the entire medical device 20, the holder may be omitted. Also, aperson of ordinary skill in the art will appreciate that medical device20 can be masked by a variety of masking methods known in the art toprevent coating certain portions of medical device 20. The holder, asone example, can be an inflatable balloon made with any material that isflexible and resilient. Latex, silicone, polyurethane, rubber (includingstyrene and isobutylene styrene), and nylon, are each examples ofmaterials that may be used in manufacturing the inflatable balloon.

Forming a coating on medical device 20 by electroplating a mixture of atherapeutic agent and a plating material may be achieved by severalmethods. In one embodiment, the therapeutic agent is dissolved into theelectrolytic solution 31 and dissociated, producing positively andnegatively charged drug ions. As one example, the ionization ofamiloride, a cationic drug has an excess of positively charged ionizedgroups that allows it to be attached to the cathode. The positivelycharged ions of the therapeutic agent are generally illustrated as 70 inFIG. 1 (labeled as “D” for drug, in this embodiment).

The electrolytic solution also ionizes into positively and negativelycharged ions. As one example, the electrolytic solution may bePd(NH₃)(NO₂)₂, which contains positively charged metal ions, Pd⁺⁺, asgenerally illustrated as 71 in FIG. 1 (labeled as “M” in thisembodiment).

At the anode 50 of the electroplating cell 30, negatively chargedelectrons are removed from the plating material 51 and flow in thedirection depicted by direction arrow A in FIG. 1 from the anode 50 tothe cathode 40. The medical device 20, electrically connected to thenegative pole of voltage source 60 and positioned as the cathode 40,receives the negatively charged electrons and thereby attracts thepositively charged ions 70 and 71 in the electrolytic solution 31. Thus,at the negatively charged cathode 40 of the electroplating cell 30, acoating is formed onto the medical device 20 by electroplating a mixtureof the therapeutic agent and plating material.

The plating material 51, electrically connected to the positive pole ofvoltage source 60, as anode 50, becomes positively charged as electronsare removed. For example, if the plating material 51 were Iron metal,the Iron would oxidize into a positively charged state as electronstravel towards the cathode 40. The Iron metal anode, in its positivelycharged state, would then dissolve as Fe⁺⁺ into the electrolyticsolution 31, thereby replacing the Fe⁺⁺ that is plated out of theelectrolytic solution 31 (where the solution is FeSO₄ which ionizes intoFe⁺⁺ and SO₄ ⁻⁻) onto the medical device 20. The anode material caneither be the metal to be deposited (as in the example above, where theelectrode reaction is the electrodissolution of Fe that continuouslysupplies Fe ions), or the anode can be an inert material where theanodic reaction is oxygen evolution (in which the plating solution mayeventually be depleted of metal ions). In some cases, the anode materialmay not be the same material as the plating material (e.g., Pd), inwhich case the electroplating reaction reduces metal ions from aqueous,organic, or fused salt electrolytes. This type of reaction at thecathode may generally be represented by the following equation:M ^(+n) +ne ⁻ =>MA corresponding reaction occurs at the anode.

Some examples, among others, of therapeutic agents that may be ionizedare cationic drugs, such as amiloride, digoxin, morphine, procainamide,quinidine, quinine, ranitidine, triamterene, trimethoprim, andvancomycin. One of ordinary skill in the art will appreciate that avariety of other acid-stable drugs that may be dissociated in anelectrolytic solution into ions may be used. Selection of the drug andplating formulation may be limited to a combination that does not resultin the destruction of the drug during the electroplating process.Further, since electroplating, when compared to other processes such assputtering, may be conducted at ambient or relatively low temperatures,less drug may be destroyed.

In another embodiment, the ratio of metal ions 71 and therapeutic agentions 70 in the electrolytic solution 31 can be varied to control theamount and concentration of the therapeutic agent in the coating. Askilled artisan can appreciate that the ratio of metal to therapeuticagent ions can be controlled, for example, by initially dissolving agreater concentration of therapeutic agent into the electrolyticsolution 31.

In another embodiment, the voltage can be varied to intermittently platemetal and therapeutic agent coating layers. One of ordinary skill in theart will appreciate that the plating material 51 and therapeutic agentmay be selected such that they have disparate plating voltages. Thus,alternating coatings of metal and therapeutic agent layers can beachieved by first setting the voltage source 60 at the specific platingvoltage for plating metal ions, and then subsequently changing thevoltage of voltage source 60 to plate therapeutic agent ions.

In still another embodiment, two or more therapeutic agents withdisparate plating voltages may be dissolved and ionized in theelectrolytic solution 31. By varying the voltage of voltage source 60alternately between the different plating voltages, multiple coatings oftwo or more therapeutic agents may be plated in a unitary coatingprocess step without requiring an intermediate drying step betweenapplication of coating layers.

In yet another embodiment, the surface of the medical device is firsttreated to create a porous layer to increase the amount of thetherapeutic agent that may be electroplated onto the medical device.Thereafter, the coating is formed by electroplating the therapeuticagent onto the treated surface and into the pores of the porous layer.Due to the large surface area of the porous structure, large amount oftherapeutic agents can be drawn into the pores, and a largerconcentration of therapeutic agent can be applied.

The porous layer can be created by several methods, including vapordeposition processes, CVD, PVD, plasma deposition, electroplating,sintering, sputtering or other methods known in the art. The depositedporous material may be the same as the substrate or the metal beingelectroplated. The amount of plated drug which can be loaded onto theporous layer is much greater than the amount of plated drug that can beloaded onto a flat surface. This is because the pores not only add moresurface area upon which to load the plated drug, but also because thevolume of the pores are filled with the plated drug. For example, thesurface area of I gram of non-porous gold is about 8×10⁻⁵ m²/g, whereasthe surface area of nanoporous gold made by a de-alloying process isabout 2 m²/g. Although this embodiment described above involves atwo-step process, by forming the porous layer first at relatively hightemperatures, or annealing the substrate at relatively high temperaturesto enhance the adhesion, the second step of therapeutic agent platingcan be done at a lower temperature or room temperature. The shape of thepores in the porous surface may serve as a means to control the releaserate of the therapeutic agent. For example, a pore with a narrow openingand a wide bottom may release drugs more slowly than a pore with a wideopening and a narrow bottom. Also, a pore with a jagged inner surface,or with varying narrow and wide radiuses throughout the depth of thepore, or a pore with an elongated tortuous passageway may also serve tometer the release rate of the drug.

Alternatively, the process of forming the porous layer and plating thetherapeutic agent may be conducted in one step. Since the porous layercan be created by electroplating, a mixture of the therapeutic agent andporous plating material may be electroplated in one step similar to theelectroplating process described herein.

Also, the coating density may vary depending on the concentration of thetherapeutic agent in the coating layer. If the concentration isrelatively high, the coating can be denser. Further, the concentrationof the therapeutic agent may be higher at the outer surface of thetreated layer than the interior porous layers. Thus, more therapeuticagents may be released first from the outer surface once the device isdeployed in a patient, which may be preferred. Thereafter, the releasecan be slower as the therapeutic agent is released from the interiorporous layers. One of ordinary skill in the art will appreciate that theconcentration of the therapeutic agent in the coating layer can bevaried by increasing or decreasing the porosity of the porous layer,which permits more or less of the therapeutic agent to be plated, upontreating the surface of the medical device.

By first treating the surface of the medical device to create aninterconnected porous network layer of coating, therapeutic agents maybe released in a slow and controlled manner. The therapeutic agent isreleased through the path in the metal matrix. Further, by creating anano-porous layer, the therapeutic agent may be applied without apolymer binder. The treatment process of creating a porous layer isfurther described in the following pending patent applications:“Functional Coatings and Designs for Medical Implants,” by Weber,Holman, Eidenschink and Chen, application Ser. No. 10/759,605; and“Medical Devices Having Nanostructured Regions for Controlled TissueBiocompatibility and Drug Delivery,” by Helmus, Xu and Ranada, filed oneven date with the instant application. These applications areincorporated herein.

In FIG. 2, an apparatus for coating a medical device in accordance withanother embodiment of the present invention is illustrated. In thisembodiment, generally designated as 20, an electroplating cell 30 isshown which contains an electrolytic solution 31 having metal ions 71and drug particles, generally illustrated as 72 in FIG. 2, suspendedwithin the electrolytic solution 31. Where the desired therapeutic agentor drug coating cannot be dissolved in the electrolytic solution 31 andbecome ionized, the therapeutic agent or drug may be produced in fineparticles, e.g. nano-meter sized particles, and suspended. During theplating process, these particles will become trapped by the metal ions71, and will plate to the medical device 20—similar to the way thatcontamination elements are trapped by plating material ions and becomeplated to a substrate in conventional electroplating processes. Theamount of the therapeutic agent or drug particles 72 that are depositedonto the surface of medical device 20 varies with the concentration ofthe therapeutic agent or drug suspended in the electrolytic platingsolution 31. One of ordinary skill in the art will appreciate thatparticles of two or more therapeutic agents or drugs may be suspended inthe electrolytic solution to allow multiple coatings.

The medical devices used in conjunction with the present inventioninclude any device amenable to the coating processes described herein.The medical device, or portion of the medical device, to be coated orsurface modified may be made of metal, polymers, ceramics, composites orcombinations thereof. Whereas the present invention is described hereinwith specific reference to a vascular stent, other medical deviceswithin the scope of the present invention include any devices which areused, at least in part, to penetrate the body of a patient. Non-limitingexamples of medical devices according to the present invention includecatheters, guide wires, balloons, filters (e.g., vena cava filters),stents, stent grafts, vascular grafts, intraluminal paving systems, softtissue and hard tissue implants, such as orthopedic reair plates androds, joint implants, tooth and jaw implants, metallic alloy ligatures,vascular access ports, artificial heart housings, heart valve struts andstents (used in support of biologic heart valves), aneurysm fillingcoils and other coiled coil devices, trans myocardial revascularization(“TMR”) devices, percutaneous myocardial revascularization (“PMR”)devices, hypodermic needles, soft tissue clips, holding devices, andother types of medically useful needles and closures, and other devicesused in connection with drug-loaded polymer coatings. Such medicaldevices may be implanted or otherwise utilized in body lumina and organssuch as the coronary vasculature, esophagus, trachea, colon, biliarytract, urinary tract, prostate, brain, lung, liver, heart, skeletalmuscle, kidney, bladder, intestines, stomach, pancreas, ovary,cartilage, eye, bone, and the like. Any exposed surface of these medicaldevices may be coated with the methods and apparatuses of the presentinvention.

The coating materials used in conjunction with the present invention areany desired, suitable substances. In some embodiments, the coatingmaterials comprise therapeutic agents, applied to the medical devicesalone or in combination with solvents in which the therapeutic agentsare at least partially soluble or dispersible or emulsified, and/or incombination with polymeric materials as solutions, dispersions,suspensions, latices, etc. The solvents may be aqueous or non-aqueous.Coating materials with solvents may be dried or cured, with or withoutadded external heat, after being deposited on the medical device toremove the solvent. The therapeutic agent may be any pharmaceuticallyacceptable agent such as a non-genetic therapeutic agent, a biomolecule,a small molecule, or cells. The coating on the medical devices mayprovide for controlled release, which includes long-term or sustainedrelease, of a therapeutic agent.

Exemplary non-genetic therapeutic agents include anti-thrombogenicagents such as heparin, heparin derivatives, prostaglandin (includingmicellar prostaglandin E1), urokinase, and PPack (dextrophenylalanineproline arginine chloromethylketone); anti-proliferative agents such asenoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus,monoclonal antibodies capable of blocking smooth muscle cellproliferation, hirudin, and acetylsalicylic acid; anti-inflammatoryagents such as dexamethasone, rosiglitazone, prednisolone,corticosterone, budesonide, estrogen, estrodiol, sulfasalazine,acetylsalicylic acid, mycophenolic acid, and mesalamine;anti-neoplastic/anti-proliferative/anti-mitotic agents such aspaclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,vincristine, epothilones, endostatin, trapidil, halofuginone, andangiostatin; anti-cancer agents such as antisense inhibitors of c-myconcogene; anti-microbial agents such as triclosan, cephalosporins,aminoglycosides, nitrofurantoin, silver ions, compounds, or salts;biofilm synthesis inhibitors such as non-steroidal anti-inflammatoryagents and chelating agents such as ethylenediaminetetraacetic acid,O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid andmixtures thereof, antibiotics such as gentamycin, rifampin, minocyclin,and ciprofolxacin; antibodies including chimeric antibodies and antibodyfragments; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; nitric oxide; nitric oxide (NO) donors such as lisidomine,molsidomine, L-arginine, NO-carbohydrate adducts, polymeric oroligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Argchloromethyl ketone, an RGD peptide-containing compound, heparin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, enoxaparin, hirudin,warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, plateletaggregation inhibitors such as cilostazol and tick antiplatelet factors;vascular cell growth promotors such as growth factors, transcriptionalactivators, and translational promotors; vascular cell growth inhibitorssuch as growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogeneus vascoactive mechanisms; inhibitors ofheat shock proteins such as geldanamycin; and any combinations andprodrugs of the above.

Exemplary biomolecules include peptides, polypeptides and proteins;oligonucleotides; nucleic acids such as double or single stranded DNA(including naked and cDNA), RNA, antisense nucleic acids such asantisense DNA and RNA, small interfering RNA (siRNA), and ribozymes;genes; carbohydrates; angiogenic factors including growth factors; cellcycle inhibitors; and anti-restenosis agents. Nucleic acids may beincorporated into delivery systems such as, for example, vectors(including viral vectors), plasmids or liposomes.

Non-limiting examples of proteins include monocyte chemoattractantproteins (“MCP-1) and bone morphogenic proteins (“BMP's”), such as, forexample, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8,BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPSare any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs canbe provided as homdimers, heterodimers, or combinations thereof, aloneor together with other molecules. Alternatively, or in addition,molecules capable of inducing an upstream or downstream effect of a BMPcan be provided. Such molecules include any of the “hedghog” proteins,or the DNA's encoding them. Non-limiting examples of genes includesurvival genes that protect against cell death, such as anti-apoptoticBc1-2 family factors and Akt kinase and combinations thereof.Non-limiting examples of angiogenic factors include acidic and basicfibroblast growth factors, vascular endothelial growth factor, epidermalgrowth factor, transforming growth factor α and β, platelet-derivedendothelial growth factor, platelet-derived growth factor, tumornecrosis factor α, hepatocyte growth factor, and insulin like growthfactor. A non-limiting example of a cell cycle inhibitor is a cathespinD (CD) inhibitor. Non-limiting examples of anti-restenosis agentsinclude p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys,thymidine kinase (“TK”) and combinations thereof and other agents usefulfor interfering with cell proliferation.

Exemplary small molecules include hormones, nucleotides, amino acids,sugars, and lipids and compounds have a molecular weight of less than100 kD.

Exemplary cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells. Cells can be of humanorigin (autologous or allogenic) or from an animal source (xenogenic),or genetically engineered.

Any of the therapeutic agents may be combined to the extent suchcombination is biologically compatible.

Any of the above mentioned therapeutic agents may be incorporated into apolymeric coating on the medical device or applied onto a polymericcoating on a medical device. The polymers of the polymeric coatings maybe biodegradable or non-biodegradable. Non-limiting examples of suitablenon-biodegradable polymers include polyisobutylene copolymers andstyrene-isobutylene-styrene block copolymers such asstyrene-isobutylene-styrene tert-block copolymers (SIBS);polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone;polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinylethers; polyvinyl aromatics; polyethylene oxides; polyesters includingpolyethylene terephthalate; polyamides; polyacrylamides; polyethersincluding polyether sulfone; polyalkylenes including polypropylene,polyethylene and high molecular weight polyethylene; polyurethanes;polycarbonates, silicones; siloxane polymers; cellulosic polymers suchas cellulose acetate; polymer dispersions such as polyurethanedispersions (BAYHDROL®); squalene emulsions; and mixtures and copolymersof any of the foregoing.

Non-limiting examples of suitable biodegradable polymers includepolycarboxylic acid, polyanhydrides including maleic anhydride polymers;polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes;polylactic acid, polyglycolic acid and copolymers and mixtures thereofsuch as poly(L-lactic acid) (PLLA), poly(D,L,-lactide), poly(lacticacid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone;polypropylene fumarate; polydepsipeptides; polycaprolactone andco-polymers and mixtures thereof such aspoly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate;polyhydroxybutyrate valerate and blends; polycarbonates such astyrosine-derived polycarbonates and arylates, polyiminocarbonates, andpolydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates;polyglycosaminoglycans; macromolecules such as polysaccharides(including hyaluronic acid; cellulose, and hydroxypropylmethylcellulose; gelatin; starches; dextrans; alginates and derivativesthereof), proteins and polypeptides; and mixtures and copolymers of anyof the foregoing. The biodegradable polymer may also be a surfaceerodable polymer such as polyhydroxybutyrate and its copolymers,polycaprolactone, polyanhydrides (both crystalline and amorphous),maleic anhydride copolymers, and zinc-calcium phosphate.

In a preferred embodiment, the polymer is polyacrylic acid available asHYDROPLUS® (Boston Scientific Corporation, Natick, Mass.), and describedin U.S. Pat. No. 5,091,205, the disclosure of which is incorporated byreference herein. In a more preferred embodiment, the polymer is aco-polymer of polylactic acid and polycaprolactone.

Such coatings used with the present invention may be formed by anymethod known to one in the art. For example, an initial polymer/solventmixture can be formed and then the therapeutic agent added to thepolymer/solvent mixture. Alternatively, the polymer, solvent, andtherapeutic agent can be added simultaneously to form the mixture. Thepolymer/solvent mixture may be a dispersion, suspension or a solution.The therapeutic agent may also be mixed with the polymer in the absenceof a solvent. The therapeutic agent may be dissolved in thepolymer/solvent mixture or in the polymer to be in a true solution withthe mixture or polymer, dispersed into fine or micronized particles inthe mixture or polymer, suspended in the mixture or polymer based on itssolubility profile, or combined with micelle-forming compounds such assurfactants or adsorbed onto small carrier particles to create asuspension in the mixture or polymer. The coating may comprise multiplepolymers and/or multiple therapeutic agents.

The release rate of drugs from drug matrix layers is largely controlled,for example, by variations in the polymer structure and formulation, thediffusion coefficient of the matrix, the solvent composition, the ratioof drug to polymer, potential chemical reactions and interactionsbetween drug and polymer, the thickness of the drug adhesion layers andany barrier layers, and the process parameters, e.g., drying, etc. Thecoating(s) applied by the methods and apparatuses of the presentinvention may allow for a controlled release rate of a coating substancewith the controlled release rate including both long-term and/orsustained release.

The coatings of the present invention are applied such that they resultin a suitable thickness, depending on the coating material and thepurpose for which the coating(s) is applied. It is also within the scopeof the present invention to apply multiple layers of polymer coatingsonto the medical device. Such multiple layers may contain the same ordifferent therapeutic agents and/or the same or different polymers,which may perform identical or different functions. Methods of choosingthe type, thickness and other properties of the polymer and/ortherapeutic agent to create different release kinetics are well known toone in the art.

The medical device may also contain a radio-opacifying agent within itsstructure to facilitate viewing the medical device during insertion andat any point while the device is implanted. Non-limiting examples ofradio-opacifying agents are bismuth subcarbonate, bismuth oxychtoride,bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.

In addition to the previously described coating layers and theirpurposes, in the present invention the coating layer or layers may beapplied for any of the following additional purposes or combination ofthe following purposes: to alter surface properties such as lubricity,contact angle, hardness, or barrier properties; to improve corrosion,humidity and/or moisture resistance; to improve fatigue, mechanicalshock, vibration, and thermal cycling; to change/control composition atsurface and/or produce compositionally graded coatings; to applycontrolled crystalline coatings; to apply conformal pinhole freecoatings; to minimize contamination; to change radiopacity; to impactbio-interactions such as tissue/blood/fluid/cell compatibility,anti-organism interactions (fungus, microbial, parasiticmicroorganisms), immune response (masking); to control release ofincorporated therapeutic agents (agents in the base material, subsequentlayers or agents applied using the above techniques or combinationsthereof); or any combinations of the above using single or multiplelayers.

One of skill in the art will realize that the examples described andillustrated herein are merely illustrative, as numerous otherembodiments may be implemented without departing from the spirit andscope of the present invention.

1. A method for coating at least a portion of a medical devicecomprising: ionizing a therapeutic agent in an electrolytic solution;and electroplating a mixture of a plating material and the ionizedtherapeutic agent onto the medical device, thereby forming a coatingwith the therapeutic agent on a medical device.
 2. The method of claim 1further comprising dissolving a measured amount of therapeutic agent inthe electrolytic solution.
 3. The method of claim 1 wherein the step ofelectroplating comprises introducing a voltage source having a measuredvoltage.
 4. The method of claim 3 further comprising regulating themixture of the therapeutic agent and plating material by changing thevoltage.
 5. The method of claim 1 further comprising treating a surfaceof the medical device to be coated.
 6. The method of claim 5 wherein thestep of treating a surface to be coated comprises creating a poroussurface layer.
 7. The method of claim 6 wherein the porous surface layeris made by vapor deposition, plasma deposition, sintering, sputtering orelectroplating.
 8. The method of claim 1 wherein the plating material isgold, titanium, halfnium, halfnium oxide, zirconium, iridium, iridiumoxide, alumina, niobium, or niobium oxide.
 9. The method of claim 1wherein the electrolytic solution comprises an acid or salt of theplating metal.
 10. The method of claim 1 wherein the coating comprises apolymeric material.
 11. The method of claim 1 wherein the therapeuticagent is selected from the group consisting of pharmaceutically activecompounds, proteins, oligonucleotides, DNA compacting agents,recombinant nucleic acids, gene/vector systems, and nucleic acids. 12.The method of claim 1 wherein the therapeutic agent is a cationic drug.13. The method of claim 12 wherein the cationic drug is amiloride,digoxin, morphine, procainamide, quinidine, quinine, ranitidine,triamterene, trimethoprim, or vancomycin.
 14. The method of claim 1wherein the medical device is a stent.
 15. A bio-compatible medicaldevice for insertion into a body prepared according to the method ofclaim
 1. 16. A method for coating at least a portion of a medical devicecomprising: suspending a therapeutic agent in an electrolytic solution;and electroplating a plating material onto the medical device, whereinthe coating of plating material contains suspended therapeutic agent,thereby forming a coating with the therapeutic agent on the medicaldevice.
 17. The method of claim 16 further comprising treating a surfaceof the medical device to be coated.
 18. The method of claim 17 whereinthe step of treating a surface to be coated comprises creating a poroussurface layer.
 19. The method of claim 18 wherein the porous surfacelayer is made by vapor deposition, plasma deposition, sintering,sputtering, or electroplating.
 20. The method of claim 16 wherein thetherapeutic agent is selected from the group consisting ofpharmaceutically active compounds, proteins, oligonucleotides, DNAcompacting agents, recombinant nucleic acids, gene/vector systems, andnucleic acids.
 21. The method of claim 16 wherein the medical device isa stent.
 22. A bio-compatible medical device for insertion into a bodyprepared according to the method of claim
 16. 23. A method for coatingat least a portion of a medical device comprising: providing a medicaldevice having a surface; treating the surface of the medical device;ionizing a therapeutic agent in an electrolytic solution; andelectroplating a mixture of the therapeutic agent and a plating materialonto the surface of the medical device.